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GUCY2D-Associated Leber Congenital Amaurosis: A Retrospective Natural History Study in Preparation for Trials of Novel Therapies

Bouzia, Z; Georgiou, M; Hull, S; Robson, AG; Fujinami, K; Rotsos, T; Pontikos, N; ... Michaelides, M; + view all (2019) GUCY2D-Associated Leber Congenital Amaurosis: A Retrospective Natural History Study in Preparation for Trials of Novel Therapies. American Journal of Ophthalmology 10.1016/j.ajo.2019.10.019. (In press). Green open access

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Abstract

Purpose To describe the natural history of Leber congenital Amaurosis (LCA) associated with GUCY2D variants (GUCY2D-LCA) in a cohort of children and adults, in preparation for trials of novel therapies. Design Retrospective case series. Participants Patients with GUCY2D-LCA at a single referral center. Methods Review of clinical notes, retinal imaging including fundus autofluorescence (FAF), and optical coherence tomography (OCT), electroretinography (ERG), and molecular genetic testing. Main Outcome Measures Demographic data, symptoms at presentation, visual acuity, evidence of progression, OCT and FAF findings, ERG assessment and molecular genetics. Results Twenty-one subjects with GUCY2D-LCA were included, with a mean follow up ± standard deviation (SD) of 10 ± 11.85 years. Marked reduction in visual acuity (VA) and nystagmus was documented in all patients within the first 3 years of life. Fifty-four percent (n=12) exhibited photophobia and 36% (n=8) had nyctalopia. VA was worse than hand motion in 71% of the patients (n=15). Longitudinal assessment of VA showed stability in all patients, except one patient who experienced deterioration over a follow-up of 44 years. Hyperopia was reported in 13 (71%) of the 17 subjects with available refraction data. Eighteen subjects had either normal fundus appearance (n=14) or a blonde fundus (n=3), while only 4 of the eldest subjects had mild RPE atrophy (mean, 49 years; range 40 - 54 years). OCT data were available for eleven subjects and four different grades of ellipsoid zone (EZ) integrity were identified: (i) continuous/intact EZ (n=6), (ii) focally disrupted EZ (n=2), (iii) focally disrupted with RPE changes (n=2), and (iv) diffuse EZ disruption with RPE changes (n=1). All examined subjects had stable OCT findings over the long follow-up period. Full-field ERGs showed evidence of a severe cone-rod dystrophy in 5 of 6 patients, and undetectable ERGs in one subject. Novel genotype-phenotype correlations are also reported. Conclusion GUCY2D-LCA is a severe early-onset retinal dystrophy associated with very poor VA from birth. Despite the severely affected photoreceptor function, the relatively preserved photoreceptor structure based on EZ integrity till late in the disease in the majority of subjects, suggests a wide therapeutic window for gene therapy trials.

Type: Article
Title: GUCY2D-Associated Leber Congenital Amaurosis: A Retrospective Natural History Study in Preparation for Trials of Novel Therapies
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.ajo.2019.10.019
Publisher version: https://doi.org/10.1016/j.ajo.2019.10.019
Language: English
Additional information: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Keywords: LCA, Leber Congenital Amaurosis, EOSRD, SECORD, GUCY2D, genetics, OCT, FAF, ERG, clinical trials, natural history, gene therapy
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/10085373
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